Three enzyme deficiencies have been described which are described with primary immunodeficiency diseases, all of which are associated with purine and pyrimidine cellular metabolism. Two of these, adenosine deaminase (ADA) and purine nucleoside phophorylase (PNP) are sequential enzymes in the purine salvage pathway. The fact that ADA and PNP are located on separate chromosomes and that each enzyme deficiency results in a distinct pattern of immunodeficiency, established a biochemical etiology for at least some of the primary immunodeficiency disorders and a potentially unique role for purine metabolic pathways in regulating immune function. The overall objective of this research proposal is to define the role of purine and pyrimidine metabolism in lymphocyte stimulation in normal and immunodeficient patients in order to develop a rational basis for the biochemical treatment of immunodeficiency. The three approaches which will be used are: 1) to characterize the lymphocyte response to mitogen and alloantigens in a new microassay culture system in immunodeficient patients and evaluate the effects of purine and pyrimidine metabolites on this response; 2) to develop a cell model of PNP deficiency using the microassay culture system; 3) to evaluate the effect on lymphocyte function of in vivo deoxycytidine therapy in patients with immunodeficiency in whom no alternative forms of therapy are currently available. This research will 1) provide an enhanced understanding of the mechanisms and control of immunologic function, 2) advance our knowledge regarding the relationship of enzyme deficiency to immunodeficiency disorders and 3) evaluate a new potential therapeutic modality for patients with primary immunodeficiencies.